ANTITRYPANOSOMAL ACTIVITY OF A NEW TRIAZINE DERIVATIVE, SIPI-1029, IN-VITRO AND IN MODEL INFECTIONS

A recently developed diaminotriazine derivative [O,O '-bis( 1,2-dihydr o-2,2-tetramethylene-4,6-diamino-S- triazin-1-yl)-1,6-hexanediol dihyd rochloride; T-46; SIPI 1029] was examined for activity against African trypanosomes in in vitro and in vivo model systems, In vitro, SIPI 10 29 was 50% inhibitory for growth of bloodstream trypomastigotes of fou r strains of Trypanosoma brucei brucei and Trypanosoma brucei rhodesie nse at 0.15 to 2.15 nhl (50% inhibitory concentrations). In in vivo mo use laboratory models of T. b. rhodesiense clinical isolate infections , SIPI 1029 was curative for 12 of 13 isolates at less than or equal t o 10 mg/kg of body weight/day for 3 days, In eight infections, a singl e dose was greater than or equal to 60% curative, and in six of these, a dose of less than or equal to 5 mg/kg was sufficient for greater th an or equal to 60% cure rates. A number of these isolates were resista nt to the standard trypanocide melarsoprol (Arsobal) and/or the diamid ines diminazene aceturate (Berenil) and pentamidine, SIPI 1029 was als o curative in combination with DL-alpha-difluoromethylornithine (Ornid yl) in a T, b, brucei central nervous system model infection, Some evi dence of toxicity was found in dosage regimens of 10 mg/kg/day for 2 o r 3 days in which deaths were observed in 6 of 65 animals given this d osage regimen. The activity of SIPI 1029 in this study indicates that this class of compounds (diaminotriazines) should be explored as leads for new human and veterinary trypanocides.